Process for producing stabilized pharmaceutical composition

ABSTRACT

The pharmaceutical composition of the invention, which comprises a benzimidazole compound of the formula ##STR1## wherein R 1  is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio or alkylsulfinyl, R 2  is hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl or alkylsulfonyl, R 3  and R 5  are the same or different and each is hydrogen, alkyl, alkoxy or alkoxyalkoxy, R 4  is hydrogen, alkyl, alkoxy which may optionally be fluorinated, or alkoxyalkoxy, and m is an integer of 0 through 4, and a basic inorganic salt stabilizing agent, is physically stable. Magnesium and calcium basic inorganic salt stabilizing agents are particularly useful.

This application is a divisional of Ser. No. 09/196,664 filed Nov. 19, 1998, now U.S. Pat. No. 6,017,560 which is a continuation of Ser. No. 08/810,951 filed Feb. 27, 1997 now U.S. Pat. No. 5,879,708, which is a continuation of Ser. No. 08/488,152, filed Jun. 7, 1995 (now U.S. Pat. No. 5,639,478), which is a continuation of Ser. No. 08/120,867, filed on Sep. 10, 1993 (now U.S. Pat. No. 5,433,959), which is a continuatioin of Ser. No. 07/793,091, filed Nov. 15, 1991 (now abandoned), which is a divisional of Ser. No. 07/575,897, filed Aug. 31, 1990 (now U.S. Pat. No. 5,093,132), which is a continuation of Ser. No. 07/014,303, filed Feb. 13, 1987 (now U.S. Pat. No. 5,045,321) which application(s) are incorporated herein by reference.

This invention relates to a pharmaceutical composition which comprises 2-[(2-pyridyl)methylsulphinyl]benzimidazole or a derivative thereof (hereinafter sometimes referred to collectively as "benzimidazole compounds"), particularly the derivatives 2-[[3-methyl-4-(2,2,2-trifluoromethoxy)-2-pyridyl]methylsulfinyl]benzimidazole and 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazole, or a pharmaceutically acceptable salt thereof, which is useful as an antiulcer agent. The composition is stabilized by incorporation of an effective amount of a basic inorganic salt stabilizing agent, with basic inorganic salts of magnesium, calcium, potassium and sodium being useful, the magnesium can calcium salts being preferred.

Certain benzimidazole compounds are recently under clinical study as gastric acid secretion inhibitors. They serve as therapeutic agents for digestive ulcer. Their principal pharmacological effect consists in gastric acid secretion suppression based on (H⁺ +K⁺)-ATPase inhibition and is more potent and durable as compared with histamine H₂ receptor antagonists such as cimetidine and ranitidine. They also have gastric mucosa protecting activity. Therefore, they have attracted attention as next-generation potent therapeutic agents for digestive ulcer.

Those benzimidazole compounds which are described in Japanese Unexamined patent laid open Nos. 62275/77, 141783/79, 53406/82, 135881/83, 192880/83 and 181277/84, corresponding to U.S. Pat. No. 4,045,563, U.S. Pat. No. 4,255,431, European Patent Publication No. 45,200, U.S. Pat. No. No. 4,472,409, European Patent Publication No. 5,129 and G.B. Patent Publication No. 2,134,523A, respectively, among others are known to have antiulcer activity.

These compounds, however, are poor in stability. In solid state, they are susceptible to heat, moisture and light and, in aqueous solution or suspension, their stability decreases with decreasing pH. In dosage forms, i.e. tablets, powders, fine granules, granules and capsules, said compounds are apt to interact with other components contained in said dosage forms and accordingly are in less stable state as compared with the case where they occur alone. Thus, the content decreases and the color changes significantly in the manufacturing process of dosage form and with the lapse of time. Microcrystalline cellulose, polyvinylpyrrolidone (PVP) , carboxymethylcellulose calcium, polyethylene glycol 6000 and Pluronic F68 (polyoxyethylene-polyoxypropylene copolymer), for instance are dosage form components adversely affecting the stability of said compounds. Furthermore, in the case of coated tablets and coated granules among the above dosage forms, enteric coating bases such as cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate and Eudragit (methacrylic acid-acrylic acid copolymer) have poor compatibility with said compounds and cause content decrease and color change. Nevertheless, one or more of these components or ingredients, which, as mentioned above, can produce adverse effects on the stability of said compounds, are essential in the manufacture of oral preparations and therefore difficulties are inevitably encountered in dosage form manufacture.

The prior art avoids the above-mentioned stability problem by using said benzimidazole compounds in a salt form, say in the form of a lithium, sodium, potassium, magnesium, calcium or titanium salt [Japanese Unexamined Patent laid open No. 167587/84 (European Patent Publication No. 124,495A)]

However, the above prior art method requires, for the stabilization of the benzimidazole compounds, a step of converting said compounds to such a salt form as mentioned above in advance.

In view of the above, the present inventors made investigations in an attempt to stabilize pharmaceutical preparations containing benzimidazole compounds and, as a result, have completed the present invention.

Thus, this invention relates to

(1) A pharmaceutical composition which comprises 2-[(2-pyridyl)methylsulfinyl]benzimidazole or a derivative thereof, which has an antiulcer activity, and a basic inorganic salt of magnesium and/or a basic inorganic salt of calcium, and

(2) A method of Producing a stabilized pharmaceutical composition which comprises incorporating a basic inorganic salt of magnesium and/or a basic inorganic salt of calcium in a pharmaceutical composition containing 2-[(2-pyridylmethylsulfinyl]benzimidazole or a derivative thereof, which has an antiulcer activity.

The benzimidazole compounds having an antiulcer activity which are to be used in the practice of the invention are those compounds which are described in the above-cited laid-open patent specifications, for instance and are represented by the formula ##STR2## wherein R¹ is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio or alkylsulfinyl, R² is hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl or alkylsulfonyl, R³ and R⁵ are the same or different and each is hydrogen, alkyl, alkoxy or alkoxyalkoxy, R⁴ is hydrogen, alkyl, alkoxy which may optionally be fluorinated, or alkoxyalkoxy, and m is an integer of 0 through 4.

The compounds of the formula(I) can be produced by the methods described in the above-cited laid-open patent specifications or modifications thereof.

In the following, brief mention is made of the substituents in those compounds which have the formula (I) and are already known.

Referring to R¹ in the above formula, C₁₋₇ alkyls may be mentioned as the alkyl represented by R¹ ; C₁₋₄ alkoxys as the alkoxy moiety of the carboalkoxy; C₁₋₄ alkoxys as the alkoxy moiety of the carboalkoxyalkyl and C₁₋₄ alkyls as the alkyl moiety; C₁₋₄ alkyls as the alkyl moiety of the carbamoylalkyl; C₁₋₅ alkoxys as the alkoxy; C₁₋₇ alkyls as the alkyl moiety of the hydroxyalkyl; C₁₋₄ alkanoyls as the acyl; phenyl as the aryl; phenyl as the aryl moiety of the aryloxy; C₁₋₆ alkyls as the alkyl moiety of the alkylthio; and C₁₋₆ alkyls as the alkyl moiety of the alkylsulfinyl.

Referring to R², C₁₋₅ alkyls may be mentioned as the alkyl represented by R² ; C₁₋₄ alkanoyls as the acyl; C₁₋₄ alkoxys as the alkoxy moiety of the carboalkoxy; C₁₋₄ alkyls as the alkyl moiety of the alkylcarbamoyl; C₁₋₄ alkyls as each of the alkyl moieties of the dialkylcarbamoyl; C₁₋₄ alkyls as the alkyl moiety of the alkylcarbonylmethyl; C₁₋₄ alkoxys as the alkoxy moiety of the alkoxycarbonylmethyl; and C₁₋₄ alkyls as the alkyl moiety of the alkylsulfonyl.

Referrring to R³, R⁴ and R⁵, C₁₋₄ alkyls may be mentioned as the alkyl represented by any of them; C₁₋₈ alkoxys as the alkoxy; and C₁₋₄ alkoxys as each of the alkoxy moieties of the alkoxyalkoxy.

Referring to R⁴, C₁₋₈ alkoxys may be mentioned as the alkoxy, which may optionally be fluorinated.

Among those compounds of the above formula (I), (1) the compounds of which R¹ is hydrogen, methoxy or trifluoromethyl, R² is hydrogen, R³ and R⁵ are the same or different and each is hydrogen or methyl, R⁴ is fluorinated C₂₋₅ alkoxy and m is 1, (2) the compounds of which R¹ is hydrogen, fluorine, methoxy or trifluoromethyl, R² is hydrogen, R³ is hydrogen or methyl, R⁴ is C₃₋₈ alkoxy, R² is hydrogen and m is 1, and (3) the compounds of which R¹ is hydrogen, fluorine, methoxy or trifluoromethyl, R² is hydrogen, R³ is C₁₋₈ alkoxy, R⁴ is C₁₋₈ alkoxy which may be fluorinated, R⁵ is hydrogen and m is 1.

Detailed mention is now made of the substituents in such novel compounds.

Referring to R³, the lower alkyl represented thereby is preferably C₁₋₈ lower alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy, heptyloxy or octyloxy and more preferably C₁₋₄ lower alkoxy.

Referring to R⁴, C₁₋₈ lower alkoxys may be mentioned as the lower alkoxy, which may optionally be fluorinated, and preferred examples are as mentioned above for R³. As the fluorinated lower alkoxy, there may be mentioned, for example, 2,2,2-trifluoroethoxy, 2,2,3,3,3-pentafluoropropoxy, i-(trifluoromethyl)-2,2,2-trifluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,4,4,4-hepta-fluorobutoxy and 2,2,3,3,4,4,5,5-octafluoropentoxy, and fluorinated C₂₋₄ lower alkoxys are preferred.

The position of R¹ is position 4 or position 5, preferably position 5.

Some methods of producing the above novel compounds [hereinafter referred to as compounds of formula (I')"] are described below.

Said compounds can be produced by subjecting a compound of the formula ##STR3## wherein R¹ -R⁵ are as defined above, to oxidation.

The oxidizing agent to be used is, for example, meta-chloroperbenzoic acid, peracetic acid, trifluoroperacetic acid, permaleic acid or the like peracid, sodium bromite or sodium hypochlorite. Examples of the solvent to be used in carrying out the reaction are halogenated hydrocarbons such as chloroform and dichloromethane, ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide, and water. These solvents may be used either singly or in admixture. Said oxidizing agent is used preferably in an amount approximately equivalent or slightly excessive relative to the compound (II). Thus, said agent is used in an amount of about 1-3 equivalents, more preferably about 1 to 1.5 equivalents. The reaction is carried out at a temperature from about 0° C. (ice cooling) to around the boiling point of the solvent used, generally at a temperature from about 0° C. (ice cooling) to room temperature, preferably at a temperature of about 0° C. to 10° C. The reaction time is generally about 0.1 to 24 hours, preferably about 0.1 to 4 hours.

The desired novel compounds (II) produced by the above reaction can be isolated and purified by conventional means such as recrystallization, chromatography and so on.

Said compounds may be converted to pharmacologically acceptable salts by conventional means. As such salts, there may be mentioned hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate and citrate, among others.

The novel compounds (II) can be produced by reacting a starting compound of the formula ##STR4## wherein R¹ and R² are as defined above, with a starting compound of the formula ##STR5## wherein R³ -R⁵ are as defined above and X is a halogen atom.

The halogen atom represented by X is, for example, chlorine, bromine or iodine.

The reaction is carries out advantageously in the presence of a base. As said base, there may be mentioned alkali metal hydrides such as sodium hydride and potassium hydride, alkali metals such as metallic sodium, sodium alcoholates such as sodium methoxide and sodium ethoxide, alkali metal carbonates such as potassium carbonate and sodium carbonate, and organic amines such as triethylamine, among others. As the solvent to be used in carrying out the reaction, there may be mentioned, for example, alcohols such as methanol and ethanol, and dimethylformamide. The base is used generally in an amount slightly excessive relative to the equivalent amount but may also be used in large excess. Thus, it is used in an amount of about 2-10 equivalents, preferably about 2-4 equivalents. The above reaction is carried out generally at a temperature of about 0° C. to around the boiling point of the solvent used, preferably at about 20° C. to 80° C., for a period of about 0.2-24 hours, preferably about 0.5-2 hours.

Some methods of producing the starting compounds (IV) are described below.

Among the compounds (IV), those compounds wherein R³ and R⁵ are the same or different and each is hydrogen or methyl and R⁴ is fluorinated C₂₋₅ alkoxy or C₃₋₈ alkoxy can be produced by the following process: ##STR6##

A nitro compound of the formula (V), wherein R³ and R⁵ are as defined above, is reacted with an alcohol derivative of the formula R^(4') OH (VI) wherein R^(4') is fluorinated C₂₋₅ alkyl or C₃₋₈ alkyl, in the presence of a base to give an alkoxy derivative of the formula (VII) wherein R³, R⁴ and R⁵ are as defined above. The base to be used in carrying out the reaction includes, among others, alkali metals such as lithium, sodium and potassium, alkali metal hydrides such as sodium hydride and potassium hydride, alcoholates such as potassium t-butoxide and sodium propoxide, alkali metal carbonates and hydrogen carbonates such as potassium carbonate, lithium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. The alcohol derivative to be submitted to the reaction includes, among others, propanol, isopropanol, butanol, pentanol, hexanol, 2,2,2-trifluoroethanol, 2,2,3,3,3-pentafluoropropanol, 2,2,3,3-tetrafluoropropanol, 1-(trifluoromethyl)-2,2,2-trifluoroethanol, 2,2,3,3,4,4,4-heptafluorobutanol and 2,2,3,3,4,4,5,5-octafluoropentanol. While R^(4') OH itself may be used as a solvent in carrying out the reaction, ethers such as tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, acetonitrile, dimethylformamide and hexamethylphosphoric acid triamide, for instance, may also be used as solvents. An appropriate reaction temperature may be selected within the range of about 0° C. (ice cooling) to around the boiling point of the solvent used. The reaction time is about 1-48 hours.

Heating (about 80-120° C.) of the thus-obtained compound (VII) with acetic anhydride alone or in the presence of an inorganic acid such as sulfuric acid or perchloric acid gives an 2-acetoxymethylpyridine derivative of the formula (VIII) wherein. R³, R⁴ and R⁵ are as defined above. The reaction period is generally about 0.1-10 hours.

The subsequent alkaline hydrolysis of the compound (VIII) gives a 2-hydroxymethylpyridine derivative of the formula (IX). Sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate, for instance, are usable as alkalis, and methanol, ethanol and water, among others, are usable as solvents. The reaction is generally conducted at about 20-60° C. for about 0.1-2 hours.

The compound (IX) is further halogenated with a chlorinating agent such as thionyl chloride to give a 2-halomethylpyridine derivative of the formula (IV) wherein R³, R⁴ and R⁵ are as defined above and X is chlorine, bromine or iodine. Usable as solvents are, for example, chloroform, dichloromethane and tetrachloroethane. The reaction is generally carried out at about 20-80° C. for about 0.1-2 hours.

The compound (IV) thus produced occurs in the form of a salt of hydrohalogenic acid corresponding to the halogenating agent used and it is generally preferable to subject said compound to reaction with the compound (III) immediately.

Among the compounds (V), those compounds wherein R³ is C₁₋₈ lower alkoxy, R⁴ is alkoxy which may optionally be fluorinated, and R⁵ is hydrogen can be produced by the following process: ##STR7##

Thus, maltol (X) is reacted with a alkyl halide of the formula R^(3') X in the presence of silver oxide, for instance, to give a compound of the formula (XI). Reaction of (XI) with aqueous ammonia gives a pyridone derivative of the formula (XII). Direct alkylation of the compound (XII) with an alkyl halide, or halogenation of (XII) with a halogenating agent such as phosphorus oxychloride followed by reaction of the resultant halo derivative (XIV) with a lower alcohol of the formula R^(4") OH in the presence of a base gives a compound of the formula (XIII). The compound (XIII) can be converted to the compound (IV) by direct halogenation with N-bromosuccinimide or chlorine, for instance. The compound (XIII) may also be converted to the compound (IV) by oxidizing the same with an oxidizing agent such as m-chloroperbenzoic acid, reacting the resulting compound (XV) with acetic anhydride, hydrolyzing the resulting compound (XVI) and halogenating the resulting compound (XVII) with a halogenating agent such as thionyl chloride.

The alkyl halide to be used in the Production of the compound (XI) includes, among others, methyl iodide, ethyl iodide, propyl iodide, isopropyl iodide, butyl iodide, pentyl iodide and hexyl iodide, and the alkyl halide to be used in the production of the compound (XIII) further includes, in addition to those mentioned above for use in the production of the compounds (XI), 2,2,2-trifluoroethyl iodide, 2,2,3,3,3-pentafluoropropyl iodide, 2,2,3,3-tetrafluoropropyl iodide, 1-(trifluoromethyl)-2,2,2-trifluoroethyl iodide, 2,2,3,3,4,4,4-heptafluorobutyl iodide and 2,2,3,3,4,4,5,5-octafluoropentyl iodide, for instance. Such alkyl iodides are used in an amount of about 1-10 equivalents. Silver oxide, potassium carbonate, sodium carbonate or the like is used as a deacidifying agent and dimethylformamide, dimethylacetamide or the like is used as a solvent. The reaction is generally carried out at room temperature.

The halogenating agent to De used in the production of the compound (XIV) includes, among others, phosphorus oxychloride, phosphorus pentoxide and phosphorus tribromide and is used in an amount of 1 equivalent to a large excess. The reaction is carried out at a temperature of about 50-150° C. The alcohol to be used for the conversion of compound (XIV) to compound (XIII) includes methanol and ethanol and further those alcohol derivaitves mentioned for use in process 1) and is used in an amount of 1 equivalent to a large excess, and the base includes those sodium alcoholates and potassium alcoholates which correspong to the respective alcohols as well as potassium t-butoxide, sodium hydride and so forth. An appropriate reaction temperature may be selected within the range of room temperature to the boiling point of the solvent used.

For direct bromination of the compound (XIII) with N-bromosuccinimide, the reaction is preferably carried out under light irradiation, and carbon tetrachloride, chloroform, tetrachloroethane or the like is used as a solvent.

The oxidizing agent to be used for the conversion of compound (XIII) to compound (XV) includes, among others, peracids such as meta-chloroperbenzoic acid, peracetic acid, trifluoroperacetic acid and permaleic acid as well as hydrogen peroxide. Usable as solvents for the reaction are halogenated hydrocarbons such as chloroform, and dichloromethane, ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide, acetic acid and water, for instance, and these can be used either singly or in admixture. Said oxidizing agent is preferably used in an amount of about 1 equivalent to an excess relative to the compound (XIII), more preferably about 1-10 equivalents. The reaction is carried out at a temperature of about 0° C. (ice cooling) to around the boiling point of the solvent used generally for a period of about 0.1-24 hours, preferably for about 0.1-4 hours.

The conversion of compound (XV) to compound (XVI) is effected by heating (at about 80-120° C.) the compound (XV) with acetic anhydride alone or in the presence of an inorganic acid such as sulfuric acid or perchloric acid and so on. The reaction period is generally 0.1-10 hours.

The alkali to be used in the alkaline hydrolysis of compound (XVI) to compound (XVII) includes, among others, odium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate. Methanol, ethanol and water, for instance, may be mentioned as usable solvents. The reaction is generally carried out at a temperature of about 20-60° C. for a period of about 0.1-2 hours.

For the production of compound (IV) from compound (XVII), a chlorinating agent such as thionyl chloride or an organic sulfonic or organic phosphoric acid chloride such as methanesulfonyl chloride, p-toluenesulfonyl chloride or diphenylphosphoryl chloride is used. When a chlorinating agent such as thionyl chloride is used, it is used in an amount of 1 equivalent to a large excess relative to the compound (XVII) and a solvent such as chloroform, dichloromethane or tetrachloroethane is used, and the reaction is generally carried out at a temperature of about 20-80° C. for a period of about 0.1-2 hours. When an organic sulfonic or organic phosphoric acid chloride is used, it is used in an amount of 1 equivalent to a slight excess relative to the compound (XVII) and the reaction is generally carried out in the presence of a base. As usable bases, there may be mentioned organic bases such as triethylamine and tributylamine and inorganic bases such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate. The base is used in an amount of 1 equivalent to a slight excess. As usable solvents, there may be mentioned, for example, chloroform, dichloromethane, carbon tetrachloride and acetonitrile. An appropriate reaction temperature and an appropriate reaction can be selected within the ranges of about 0° C. (ice cooling) to around the boiling point and several minutes to several hours, respectively.

The above-mentioned novel benzimidazole compounds have excellent gastric antisecretory activity, gastric mucosa-protecting activity and antiulcer activity but have low toxicity, so that they can be used in the treatment of digestive ulcers in mammals (e.g. mouse, rat, rabbit, dog, cat, human).

The basic inorganic salt stabilizing agents, which are to be used in accordance with the invention, are now described.

Especially useful basic inorganic salt stabilizing agents are basic inorganic salts of magnesium and calcium. Said basic inorganic salt of magnesium includes, among others, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg₆ Al₂ (OH)₁₆.CO₃.4H₂ O] and aluminum magnesium hydroxide [2.5MgO.Al₂ O₃.xH₂ O] and said basic inorganic salt of calcium includes, among others, precipitated calcium carbonate and calcium hydroxide. Other basic inorganic salts useful as stabilizing agents include sodium and potassium basic inorganic salts such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, as well as aluminum basic inorganic salts such as aluminum silicate. It is only required of such basic inorganic salts to show basicity (pH of not less than 7) when they are in the form of a 1% aqueous solution or suspension.

Said basic inorganic salts may be used either singly or in combination of two or more species in an amount which may vary depending on the kinds thereof but generally lies within the range of about 0.3-20 parts by weight, preferably about 0.6-7 parts by weight, per part by weight of the benzimidazole compounds.

The composition of the invention may further contain such additives as vehicles (e.g. lactose, corn starch, light silicic anhydride, microcrystalline cellulose, sucrose), binders (e.g. α-form starch, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone), disintecrating agents (e.g. carboxymethylcellulose calcium, starch, low substituted hydroxypropylcellulose), surfactants [e.g. Tween 80 (Kao-Atlas), Pluronic F68 (Asahi Denka; polyoxyethylene-polyoxypropylene copolymer], antioxidants (e.g. L-cysteine, sodium sulfite, sodium ascorbate), lubricants (e.g. magnesium stearate, talc), etc.

The composition of the invention is prepared by homogeneously admixing the above benzimidazole compound, the basic inorganic salt stabilizing agent, and the above additives.

The particle sizes of said benzimidazole compound and said inorganic salt are not especially critical in a condition that they can be homogeneously admixed. For example, preferable perticle size is about less than 100 μm, more preferable one is about less than 20 μm.

The moisture amount in the composition is preferably about 6-60%, more preferably about 20-40% as equibrium relative humidity (E.R.H). The method of admixing is optional if the benzimidazole compound can finally be in contact with the basic inorganic salt stabilizing agent evenly. Thus, for example, the additives may be admixed with a mixture of the benzimidazole compound and the basic inorganic salt stabilizing agent as prepared by preliminary admixing, or the basic inorganic salt stabilizing agent may be added to a mixture of the benzimidazole compound and the additives as prepared by preliminary admixing.

Said mixture can be made up into dosage forms suited for oral administration, such as tablets, capsules, powders, granules and fine granules, by per se known means.

Tablets, granules and fine granules may be coated by a per se known method for the purpose of masking of the taste or providing them with enteric or sustained release property. Usable as coating agents are, for example, hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylycellulose, polyoxyethylene glycol, Tween 80, Pluornic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohm, West Germany; methacrylic acid-acrylic acid copolymer) and pigments such as titanium oxide and ferric oxide.

Tablets, granules, powders, fine granules and capsules can be produced by a conventional method (e.g. the method described in the 10th edition of the Japanese Pharmacopeia under General Rules for Preparations). Thus, for example, tablets are produced by adding the basic inorganic salt stabilizing agent to a mixture of the benzimidazole compound, vehicle and disintegrant, mixing, adding a binder, granulating the mixture, adding a lubricant etc. and tableting the resultant granular composition. Granules are produced by extrusion in approximately the same manner as in the production of tablets or by coating nonpareils, which contain sucrose and corn starch, with a mixture of benzimidazole compound, a basic inorganic salt stabilizing agent, and additives (e.g. sucrose, corn starch, crystalline cellulose, hydroxypropyl-cellulose, methylcellulose, hydroxypropylmethyl-cellulose, polyvinylpyrrolidone) Capsules are produced by mere mixing and filling. The dosage forms thus obtained show excellent stability with slight changes in appearance and little decreases in content even after storage for a long period of time.

The pharmaceutical composition of the present invention as obtained in the above manner exhibits excellent gastric antisecretory, gastric mucosa-protecting and antiulcer activities and has low toxicity and therefore can be used in the treatment of digestive ulcers in mammals (e.g. mouse, rat, rabbit, dog, cat, pig, human).

The pharmaceutical composition of the invention can be orally administered for the treatment of digestive ulcers in mammals in admixture with pharmacologically acceptable carriers, vehicles, diluents and so forth and in the form of capsules, tablets, granules and some other dosage forms, as mentioned hereinabove. The dose as the benzimidazole compound lies within the range of about 0.01 mg to 30 mg/kg/day, preferably about 0.1 mg to 3 mg/kg/day.

The following reference examples and working examples as well as the experimental examples described later herein illustrate the present invention in more detail but are by no means limitative of the present invention.

REFERENCE EXAMPLE 1

A mixture of 2,3-dimethyl-4-nitropyridine-1-oxide (2.0 g), methyl ethyl ketone (30 ml), 2,2,3,3,3-pentafluoropropanol (3.05 ml), anhydrous potassium carbonate (3.29 g) and hexamethylphosphoric acid triamide (2.07 g) was heated at 70-80° C. with stirring for 4.5 days. Then, the insoluble matter was filtered off and the filtrate was concentrated. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract layer was dried over magnesium sulfate, then the solvent was distilled off, and the residue was applied to a silica gel column (50 g). Elution with chloroform-methanol (10:1) and recrystallization from ethyl acetate-hexane gave 2.4 g of 2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide as colorless needles. Melting point 148-149° C.

The following compounds (VII) were produced from the corresponding compounds (V) in the same manner as above.

    ______________________________________                                         Compounds (VII)                                                                R.sup.3    R.sup.5 R.sup.4    Melting point (° C.)                      ______________________________________                                                 CH.sub.3                                                                              H       OCH.sub.2 CF.sub.3                                                                      131.0-131.5                                    Note 1) H      H       OCH.sub.2 CH.sub.2 CH.sub.3                                                             Oil                                            Note 2) CH.sub.3                                                                              H       OCH.sub.2 CH.sub.2 CH.sub.3                                                             Oil                                            ______________________________________                                          Note 1):                                                                       NMR spectrum (CDCl.sub.3) δ: 1.01(3H, t, j=7 Hz), 1.81(2H, m),           2.50(3H, s), 3.93(2H, t, J=7 Hz), 6.50-6.80(2H, m), 8.10(1H, d, J=7 Hz)        Note 2):                                                                       NMR spectrum (CDCl.sub.3) δ: 1.07(3H, t, j=7.5 Hz), 1.65-2.02(2H,        m), 2.21(3H, s), 2.52(3H, s), 3.99(2H, t, J=6 Hz), 6.68(1H, d, j=6 Hz),        8.15(1H, d, J=6 Hz)                                                      

REFERENCE EXAMPLE 2

Concentrated sulfuric acid (2 drops) was added to a solution of 2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)-pyridine-1-oxide (2.5 a) in acetic anhydride (8 ml) and the mixture was stirred at 110° C. for 2 hours and then concentrated. The residue was dissolved in methanol (30 ml), 2 N aqueous sodium hydroxide (20 ml) was added, and the mixture was stirred at room temperature for 2 hours. After concentration, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, the solvent was then distilled off, and the residue was applied to a silica gel (50 g) column. Elution with chloroform-methanol (10:1) and recrystallization from isopropyl ether gave 1.6 g of 2-hydroxymethyl-3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-pyridine as a brown oil.

NMR spectrum (CDCl₃) δ: 2.07 (3H, s), 4.28 (1H, brs), 4.49 (2H, t, J=12 Hz), 4.67 (2H, s), 6.69 (1H, d, J=5 Hz), 8.34 (1H, d, J=5 Hz)

The following compounds (IX) were produced from the corresponding compounds (VII) in the same manner as mentioned above.

    ______________________________________                                         Compounds (IX)                                                                 R.sup.3    R.sup.5 R.sup.4    Melting point (° C.)                      ______________________________________                                                 CH.sub.3                                                                              H       OCH.sub.2 CF.sub.3                                                                      93.5-94.0                                      Note 1) H      H       OCH.sub.2 CH.sub.2 CH.sub.3                                                             Oil                                            Note 2) H      CH.sub.3                                                                               OCH.sub.2 CH.sub.2 CH.sub.3                                                             Oil                                            ______________________________________                                          Note 1)                                                                        NMR spectrum (CDCl.sub.3) δ: 1.0(3H, t, J=7.5 Hz), 1.79(2H, m),          3.92(2H, t, J=6 Hz), 4.51-4.90(1H, br), 4.68(2H, s), 6.68(1H, dd, J=2 and      6 Hz), 6.80(1H, d, J=2 Hz), 8.28(1H, d, J=6 Hz)                                Note 2)                                                                        NMR spectrum (CDCl.sub.3) δ: 1.03(3H, t, J=7.5 Hz), 1.82(2H, m),         2.02(3H, s), 3.95(2H, t, J=6 Hz), 4.62(2H, s), 5.20(1H, brd, s), 6.68(1H,      d, J=6 Hz), 8.25(1H, d, J=6 Hz)                                          

REFERENCE EXAMPLE 3

Thionyl chloride (0.2 ml) was added to a solution of 2-hydroxymethyl-3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-pyridine (350 mg) in chloroform (10 ml) and the mixture was refluxed for 30 minutes and then concentrated. The residue was dissolved in methanol (5 ml) and the solution was added to a mixture of 2-mercaptobenzimidazole (200 mg), 28% sodium methoxide solution (1 ml) and methanol (6 ml). The resultant mixture was refluxed for 30 minutes. The methanol was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with dilute sodium hydroxide solution and dried over magnesium sulfate. The solvent was then distilled off, and the residue was applied to a silica gel (20 g) column. Elution with ethyl acetate-hexane (2:1) and recrystallization from ethyl acetate-hexane gave 370 mg of 2-[[3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl]-methylthio]benzimidazole hemihydrate as colorless plates. Melting point 145-146° C.

The following compounds (II) were produced by reacting the compound (III) with the corresponding compound (IV) in the same manner as mentioned above.

    ______________________________________                                         Compounds (II)                                                                 R.sup.1 R.sup.2                                                                               R.sup.3                                                                               R.sup.5                                                                             R.sup.4  Melting point (° C.)                ______________________________________                                               H     H      CH.sub.3                                                                            H    OCH.sub.2 CF.sub.3                                                                      149-150                                        H     H      H    H    OCH.sub.2 CH.sub.2 CH.sub.3                                                             84-86                                    Note) H     H      CH.sub.3                                                                            H    OCH.sub.2 CH.sub.2 CH.sub.3                                                             Oil                                      ______________________________________                                          Note)                                                                          NMR spectrum (CDCl.sub.3) δ: 0.98(3H, t, J=7.5 Hz), 1.54-1.92(2H,        m), 2.15(3H, s), 3.80(2H, t, J=6 Hz), 4.43(2H, s), 6.55(1H, d, J=6 Hz),        7.09(2H, m), 7.50(2H, m), 8.21(1H, d, J=6 Hz)                            

REFERENCE EXAMPLE 4

A solution of m-chloroperbenzoic acid (1.3 g) in chloroform (15 ml) was added dropwise to a solution of 2-[[3-methyl-4-(2,2,3,3,3-pentafuloropropoxy)-2-pyridyl]-methylthio]benzimidazole (2.2 g) in chloroform (20 ml) with ice cooling over 30 minutes and, then, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated. The concentrate was applied to a silica gel (50 g) column. Elution with ethyl acetate and recrystallization from acetone-isopropyl ether gave 1.78 g of 2-[[3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl]methylsulfinyl]benzimidazole [hereinafter sometimes referred to as compound (A)] as pale yellow prisms. Melting point 161-163° C. (decomposition).

The following compounds (I) [hereinafter sometimes referred to as compound (B), compound (C) and compound (D), respectively] were produced in the same manner from the corresponding compounds (II).

    ______________________________________                                         Compounds (I)                                                                  R.sup.1                                                                               R.sup.2                                                                              R.sup.3 R.sup.5                                                                            R.sup.4    Melting point (° C.)                ______________________________________                                         (B) H      H     CH.sub.3                                                                             H   OCH.sub.2 CF.sub.3                                                                        178-182 (decomp.)                        (C) H      H     H     H   OCH.sub.2 CH.sub.2 CH.sub.3                                                               123-125 (decomp.)                        (D) H      H     CH.sub.3                                                                             H   OCH.sub.2 CH.sub.2 CH.sub.3                                                               81-83                                    ______________________________________                                    

EXAMPLE 1

Of the components given below, the compound (A), magnesium hydroxide, L-cysteine, corn starch and lactose were mixed together, then microcrystalline cellulose, light silicic anhydride and magnesium stearate, each in half the intended amount, were added. After sufficient admixing, the mixture was compression-molded on a dry granulator (roller compactor; Freund, Japan. The compressed mass was ground in a mortar, the resultant granular mass was sassed through a round sieve (16 mesh). The remaining portions of microcrystalline cellulose, light silicic anhydride and magnesium stearate were added to the sieved mass and, after admixing, the whole mixture was made up into tablets each weighing 250 mg on a rotary tableting machine (Kikusui Seisakusho, Japan).

Composition per tablet:

    ______________________________________                                         Compound (A)           50     mg                                               Magnesium hydroxide    30     mg                                               L-Cysteine             20     mg                                               Corn starch            20     mg                                               Lactose                65.2   mg                                               Microcrystalline cellulose                                                                            60     mg                                               Light silicic anhydride                                                                               1.8    mg                                               Magnesium stearate     3.0    mg                                               Total                  250.0  mg                                               ______________________________________                                    

EXAMPLE 2

Tablets were produced in the same manner as in Example 1 except that omeprazole (Note) was used instead of the compound (A).

Note: 5-Methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazol

EXAMPLE 3

Of the components given below, the compound (B), precipitated calcium carbonate, corn starch, lactose and hydroxypropylcellulose were mixed together, water was added, and the mixture was kneaded, then dried in vacuum at 40° C. or 16 hours, around in a mortar and passed through a 16-mesh sieve to give granules. To this was added magnesium stearate and the resultant mixture was made up into tablets each weighing 200 mg on a rotary tableting machine (Kikusui Seisakusho, Japan).

Composition per tablet:

    ______________________________________                                         Compound (B)            30     mg                                              Precipitated calcium carbonate                                                                         50     mg                                              Corn starch             40     mg                                              Lactose                 73.4   mg                                              Hydroxypropylcellulose  6      mg                                              Magnesium stearate      0.6    mg                                              Water                   (0.05  ml)                                             Total                   200.0  mg                                              ______________________________________                                    

EXAMPLE 4

Tablets were produced in the same manner as in Example 3 except that timoprazole (Note) was used instead of the compound (B).

Note: 2- [(2-Pyridyl)methylsulfinyl]benzimidazole

EXAMPLE 5

The ingredients given below were mixed well in the porportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules were then dried under vacuum at 40° C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules.

Composition per 200 mg of granules

    ______________________________________                                         Compound (B)            30     mg                                              Heavy magnesium carbonate                                                                              20     mg                                              Corn starch             50     mg                                              Microcrystalline cellulose                                                                             20     mg                                              Carboxymethylcellulose calcium                                                                         10     mg                                              Hydroxypropylcellulose  10     mg                                              Pluronic F68            4      mg                                              Lactose                 26     mg                                              Water                   (0.1   ml)                                             Total                   200    mg                                              ______________________________________                                    

EXAMPLE 6

Granules were produced in the same manner as in Example 5 except that the compound (D) was used instead of the compound (B).

EXAMPLE 7

Enteric granules were produced by coating the granules obtained in Example 3 with an enteric coating composition specified below using a fluidized bed granulator (Okawara, Japan) under conditions such that the inlet air temperature was 50° C. and the granule temperature was 40° C. No. 1 hard capsules were filled with the enteric granules thus obtained in an amount of 260 mg per capsule using a capsule filling machine (Parke-Davis, U.S.A.).

Enteric coating composition:

    ______________________________________                                         Eudragit L-30D       138       mg                                                                   (solids 41.4                                                                             mg)                                             Talc                 4.1       mg                                              Polyethylene glycol 6000                                                                            12.4      mg                                              Tween 80             2.1       mg                                              Water                276       μl                                           Composition of enteric granules:                                               Granules of Example 5                                                                               200       mg                                              Enteric coat         60        mg                                              Total                260       mg                                              Composition per capsule:                                                       Enteric granules     260       mg                                              No. 1 hard capsule   76        mg                                              Total                336       mg                                              ______________________________________                                    

EXAMPLE 8

Of the components given below, the compound (3), magunesium carbonate, socrose, corn starch and crystalline cellulose were thoroughly mixed together to obtain dusting powder.

Nonpareils were put on a centrifugal fluidized coating-granulatar (CF-360 Freund, Japan) and then coated with the dusting powder as described above, while spraying hydroxypropylcellulose solution [4% (w/w)], to give spherical granules. The spherical granules were dried in vacuum at 40° C. for 16 hours and then passed through round sieves to give 12 to 32-mesh granules.

Composition per 190 mg of granules:

    ______________________________________                                         Nonpareil                 75     mg                                            Compound (B)              15     mg                                            Magnesium carbonate       15     mg                                            Sucrose                   29     mg                                            Corn starch               27     mg                                            Crystalline cellulose     27     mg                                            Hydroxypropylcellulose    2      mg                                            [Hydroxypropoxy group content: 53.4-77.5%]                                     Water                     (0.05  ml)                                           Total                     190    mg                                            ______________________________________                                    

EXAMPLE 9

Enteric granules were produced by coating the granules obtained in Example 8 with an enteric coatig composition specified below usig a fluidized bed granulator (Okawara, Japan) under conditions such that inlet air temperature was 50° C. and the granule temperature was 40° C. No. 2 hard capsules were filled with the enteric granules thus obtained in an amount of 240 mg per capsule using a capsule filling machine (Parke-Davis, USA).

Enteric coating composition:

    ______________________________________                                         Eudragit L-30D       104.7     mg                                                                   (solids 31.4                                                                             mg)                                             Talc                 9.6       mg                                              Polyethylene glycol 6000                                                                            3.2       mg                                              Tween 80             1.6       mg                                              Titanium oxide       4.2       mg                                              Water                (220      μl)                                          Composition of enteric granules:                                               Granules of Example 8                                                                               190       mg                                              Enteric coat         50        mg                                              Total                240       mg                                              Composition per capsule:                                                       Enteric granules     240       mg                                              No. 2 hard capsule   65        mg                                              Total                305       mg                                              ______________________________________                                    

EXAMPLE 10

    ______________________________________                                         Composition 1:                                                                 Compound (B)                450 g                                              Magnesium carbonate         450 g                                              Sucrose                     450 g                                              Corn starch                 450 g                                              Low substituted hydroxypropylcellulose                                                                     450 g                                              [Hydroxypropoxy group content: 10.0-13.0% (w/w),                               average particle size: no more than 30 μm]                                  Composition 2:                                                                 Sucrose                     420 g                                              Corn starch                 360 g                                              Low substituted hydroxypropylcellulose                                                                     360 g                                              [Hydroxypropoxy group content: 10.0-13.0% (w/w),                               average particle size: no more than 30 μm]                                  ______________________________________                                    

Ingredients of the above composition 1 and composition 2 were thoroughly mixed together to obtain dusting powder 1 and dusting powder 2, respectively.

2250 g of nonpareils were put on a centrifugal fluidized coating granulatar (CF-360 Freund, Japan) and then coated with the dusting powder 1, then with the dusting powder 2, while spraying 60 g of hydroxypropylcellulose in water (2000 ml) to give spherical granules.

The spherical granules were dried in vacuum at 40° C. for 16 hours and then passed through round sieve to give 12 to 32- mesh granules.

EXAMPLE 11

Enteric granules were produced by coating 3800 g of the granules obtained in Example 10 with an enteric coating composition specified below using a fluidized bed granulatar (Okawara, Japan) under conditions such that inlet air temperature was 50° C. and the granule temperature was 40° C. No. 2 hard capsules were filled with the enteric granules thus obtained in an amount of 240 mg per capsule using a filling machine (Parke-Davis, USA).

    ______________________________________                                         Enteric coating composition:                                                   Eudragit L30D-55        628    g                                               Talc                    192    g                                               Polyethylene glycol 6000                                                                               64     g                                               Titanium oxide          64     g                                               Tween 80                32     g                                               Water                   4400   ml                                              Composition per capsule:                                                       Enteric granules        240    mg                                              No. 2 hard capsule      65     mg                                              ______________________________________                                    

EXPERIMENTAL EXAMPLE 1a

The ingredients given below were mixed well in the proportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules were then dried under vacuum at 40° C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules.

Composition per 200 mg of granules

    ______________________________________                                         Compound (B)            30     mg                                              Heavy magnesium carbonate                                                                              20     mg                                              Corn starch             80     mg                                              Microcrystalline cellulose                                                                             20     mg                                              Carboxymethylcellulose calcium                                                                         10     mg                                              Hydroxypropylcellulose  10     mg                                              Pluronic F68            4      mg                                              Lactose                 26     mg                                              Water                   (0.1   ml)                                             Total                   200    mg                                              ______________________________________                                    

After storage at 50° C. and 75% RH for 1 week, the granules were observed for changes in appearance. The granules of this example showed no change in appearance.

EXPERIMENT EXAMPLE 1b

The ingredients given below were mixed well in the proportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules were then dried under vacuum at 40° C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules.

Composition per 200 mg of granules

    ______________________________________                                         Compound (B)            30     mg                                              Magnesium Oxide         20     mg                                              Corn starch             80     mg                                              Microcrystalline cellulose                                                                             20     mg                                              Carboxymethylcellulose calcium                                                                         10     mg                                              Hydroxypropylcellulose  10     mg                                              Pluronic F68            4      mg                                              Lactose                 26     mg                                              Water                   (0.1   ml)                                             Total                   200    mg                                              ______________________________________                                    

After storage at 50° C. and 75% RH for 1 week, the granules were observed for changes in appearance. The granules of this example showed no change in appearance.

EXPERIMENTAL EXAMPLE 1c

The ingredients given below were mixed well in the proportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules were then dried under vacuum at 40° C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules.

Composition per 200 mg of granules

    ______________________________________                                         Compound (B)            30     mg                                              Magnesium Metasilicate Aluminate                                                                       20     mg                                              Corn starch             80     mg                                              Microcrystalline cellulose                                                                             20     mg                                              Carboxymethylcellulose calcium                                                                         10     mg                                              Hydroxypropylcellulose  10     mg                                              Pluronic F68            4      mg                                              Lactose                 26     mg                                              Water                   (0.1   ml)                                             Total                   200    mg                                              ______________________________________                                    

After storage at 50° C. and 75% RH for 1 week, the granules ere observed for changes in appearance. The granules of this example showed no change in appearance.

EXPERIMENTAL EXAMPLE 1d

The ingredients given below were mixed well in the proportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules were then dried under vacuum at 40° C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules.

Composition per 200 mg of granules

    ______________________________________                                         Compound (B)            30     mg                                              Synthetic Hydrotalcite  20     mg                                              Corn starch             80     mg                                              Microcrystalline cellulose                                                                             20     mg                                              Carboxymethylcellulose calcium                                                                         10     mg                                              Hydroxypropylcellulose  10     mg                                              Pluronic F68            4      mg                                              Lactose                 26     mg                                              Water                   (0.1   ml)                                             Total                   200    mg                                              ______________________________________                                    

After storage at 50° C. and 75% RH for 1 week, the granules were observed for changes in appearance. The granules of this example showed no change in appearance.

EXPERIMENTAL EXAMPLE 3

The ingredients given below were mixed well in the proportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules were then dried under vacuum at 40° C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules.

Composition per 200 mg of granules

    ______________________________________                                         Compound (B)            30     mg                                              Aluminum magnesium hydroxide                                                                           20     mg                                              Corn starch             80     mg                                              Microcrystalline cellulose                                                                             20     mg                                              Carboxymethylcellulose calcium                                                                         10     mg                                              Hydroxypropylcellulose  10     mg                                              Pluronic F68            4      mg                                              Lactose                 26     mg                                              Water                   (0.1   ml)                                             Total                   200    mg                                              ______________________________________                                    

After storage at 50° C. and 75% RH for 1 week, the granules were observed for changes in appearance. The granules of this example showed no change in appearance.

EXPERIMENTAL EXAMPLE 1f

The ingredients given below were mixed well in the proportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules were then dried under vacuum at 40° C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules.

Composition per 200 mg of granules

    ______________________________________                                         Compound (B)            30     mg                                              Magnesium silicate      20     mg                                              Corn starch             80     mg                                              Microcrystalline cellulose                                                                             20     mg                                              Carboxymethylcellulose calcium                                                                         10     mg                                              Hydroxypropylcellulose  10     mg                                              Pluronic F68            4      mg                                              Lactose                 26     mg                                              Water                   (0.1   ml)                                             Total                   200    mg                                              ______________________________________                                    

After storage at 50° C. and 75% RH for 1 week, the granules were observed for changes in appearance. The granules of this example showed no change in appearance.

EXPERIMENTAL EXAMPLE 1g

The ingredients given below were mixed well in the proportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules were then dried under vacuum at 40° C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules.

Composition per 200 mg of granules

    ______________________________________                                         Compound (B)            30     mg                                              Precipitated calcium carbonate                                                                         20     mg                                              Corn starch             80     mg                                              Microcrystalline cellulose                                                                             20     mg                                              Carboxymethylcellulose calcium                                                                         10     mg                                              Hydroxypropylcellulose  10     mg                                              Pluronic F68            4      mg                                              Lactose                 26     mg                                              Water                   (0.1   ml)                                             Total                   200    mg                                              ______________________________________                                    

After storage at 50° C. and 75% RH for 1 week, the granules were observed for changes in appearance. The granules of this example showed no change in appearance.

EXPERIMENTAL EXAMPLE 1h

The ingredients given below were mixed well in the proportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules were then dried under vacuum at 40° C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules.

Composition per 200 mg of granules

    ______________________________________                                         Compound (B)            30     mg                                              Magnesium hydroxide     20     mg                                              Corn starch             80     mg                                              Microcrystalline cellulose                                                                             20     mg                                              Carboxymethylcellulose calcium                                                                         10     mg                                              Hydroxypropylcellulose  10     mg                                              Pluronic F68            4      mg                                              Lactose                 26     mg                                              Water                   (0.1   ml)                                             Total                   200    mg                                              ______________________________________                                    

After storage at 50° C. and 75% RH for 1 week, the granules were observed for changes in appearance. The granules of this example showed no change in appearance.

EXPERIMENTAL EXAMPLE 1i

The ingredients given below were mixed well in the proportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder's Marumerizer, Japan, 1,000 rpm). The spherical granules were then dried under vacuum at 40° C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules.

Composition per 200 mg of granules

    ______________________________________                                         Compound (B)            30     mg                                              Sodium carbonate        20     mg                                              Corn starch             80     mg                                              Microcrystalline cellulose                                                                             20     mg                                              Carboxymethylcellulose calcium                                                                         10     mg                                              Hydroxypropylcellulose  10     mg                                              Pluronic F68            4      mg                                              Lactose                 26     mg                                              Water                   (0.1   ml)                                             Total                   200    mg                                              ______________________________________                                    

After storage at 50° C. and 75% RH for 1 week, the granules were observed for changes in appearance. The granules of this example showed a moderate change in appearance to yellow.

EXPERIMENTAL EXAMPLE 1j

The ingredients given below were mixed well in the proportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules were then dried under vacuum at 40° C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules.

Composition per 200 mg of granules

    ______________________________________                                         Compound (B)            30     mg                                              Potassium carbonate     20     mg                                              Corn starch             80     mg                                              Microcrystalline cellulose                                                                             20     mg                                              Carboxymethylcellulose calcium                                                                         10     mg                                              Hydroxypropylcellulose  10     mg                                              Pluronic F68            4      mg                                              Lactose                 26     mg                                              Water                   (0.1   ml)                                             Total                   200    mg                                              ______________________________________                                    

After storage at 50° C. and 75% RH for 1 week, the granules were observed for changes in appearance. The granules of this example showed a moderate change in appearance to yellow.

EXPERIMENTAL EXAMPLE 1k

The ingredients given below were mixed well in the proportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules were then dried under vacuum at 40° C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules.

Composition per 200 mg of granules

    ______________________________________                                         Compound (B)            30     mg                                              Sodium hydrogen carbonate                                                                              20     mg                                              Corn starch             80     mg                                              Microcrystalline cellulose                                                                             20     mg                                              Carboxymethylcellulose calcium                                                                         10     mg                                              Hydroxypropylcellulose  10     mg                                              Pluronic F68            4      mg                                              Lactose                 26     mg                                              Water                   (0.1   ml)                                             Total                   200    mg                                              ______________________________________                                    

After storage at 50° C. and 75% RH for 1 week, the granules were observed for changes in appearance. The granules of this example showed a moderate change in appearance to yellow.

EXPERIMENTAL EXAMPLE 1l

The ingredients given below were mixed well in the proportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules were then dried under vacuum at 40° C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules.

Composition per 200 mg of granules

    ______________________________________                                         Compound (B)            30     mg                                              Magnesium chloride      20     mg                                              Corn starch             80     mg                                              Microcrystalline cellulose                                                                             20     mg                                              Carboxymethylcellulose calcium                                                                         10     mg                                              Hydroxypropylcellulose  10     mg                                              Pluronic F68            4      mg                                              Lactose                 26     mg                                              Water                   (0.1   ml)                                             Total                   200    mg                                              ______________________________________                                    

After storage at 50° C. and 75% RH for 1 week, the granules were observed for changes in appearance. The granules of this example showed a severe change in appearance, to violet.

EXPERIMENTAL EXAMPLE 1m

The ingredients given below were mixed well in the proportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules were then dried under vacuum at 40° C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules.

Composition per 200 mg of granules

    ______________________________________                                         Compound (B)            30     mg                                              Magnesium sulfate       20     mg                                              Corn starch             80     mg                                              Microcrystalline cellulose                                                                             20     mg                                              Carboxymethylcellulose calcium                                                                         10     mg                                              Hydroxypropylcellulose  10     mg                                              Pluronic F68            4      mg                                              Lactose                 26     mg                                              Water                   (0.1   ml)                                             Total                   200    mg                                              ______________________________________                                    

After storage at 50° C. and 75% RH for 1 week, the granules were observed for changes in appearance. The granules of this example showed a severe change in appearance, to violet.

EXPERIMENTAL EXAMPLE 1n

The ingredients given below were mixed well in the proportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules were then dried under vacuum at 40° C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules.

Composition per 200 mg of granules

    ______________________________________                                         Compound (B)            30     mg                                              Calcium chloride        20     mg                                              Corn starch             80     mg                                              Microcrystalline cellulose                                                                             20     mg                                              Carboxymethylcellulose calcium                                                                         10     mg                                              Hydroxypropylcellulose  10     mg                                              Pluronic F68            4      mg                                              Lactose                 26     mg                                              Water                   (0.1   ml)                                             Total                   200    mg                                              ______________________________________                                    

After storage at 50° C. and 75% RH for 1 week, the granules were observed for changes in appearance. The granules of this example showed a severe change in appearance, to violet.

EXPERIMENTAL EXAMPLE 1o

The ingredients given below were mixed well in the proportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granules were then dried under vacuum at 40° C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules.

Composition per 200 mg of granules

    ______________________________________                                         Compound (B)            30     mg                                              aluminum silicate       20     mg                                              Corn starch             80     mg                                              Microcrystalline cellulose                                                                             20     mg                                              Carboxymethylcellulose calcium                                                                         10     mg                                              Hydroxypropylcellulose  10     mg                                              Pluronic F68            4      mg                                              Lactose                 26     mg                                              Water                   (0.1   ml)                                             Total                   200    mg                                              ______________________________________                                    

After storage at 50° C. and 75% RH for 1 week, the granules were observed for changes in appearance. The granules of this example showed a moderate change in appearance, to violet.

EXPERIMENTAL EXAMPLE 1p

The ingredients given below were mixed well in the proportions given below, water was added, and the mixture was kneaded and granulated in an extruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). The granules were immediately converted to spherical form in a spheronizer (Fuji Powder's Marumerizer, Japan; 1,000 rpm) The spherical granules were then dried under vacuum at 40° C. for 16 hours and passed through round sieves to give 12- to 42-mesh granules.

Composition per 200 mg of granules

    ______________________________________                                         Compound (B)            30     mg                                              Corn starch             80     mg                                              Microcrystalline cellulose                                                                             20     mg                                              Carboxymethylcellulose calcium                                                                         10     mg                                              Hydroxypropylcellulose  10     mg                                              Pluronic F68            4      mg                                              Lactose                 46     mg                                              Water                   (0.1   ml)                                             Total                   200    mg                                              ______________________________________                                    

After storage at 50° C. and 75% RH for 1 week, the granules were observed for changes in appearance. The granules of this example showed a severe change in appearance, to violet.

EXPERIMENTAL EXAMPLE 2

Granules were produced in the same manner as in Example 5 except that the compound (A), the compound (C), the compound (D), omeprazole or timoprazole was used instead of the compound (B). After storage at 50° C. and 75% RH for 1 week, they were observed for changes in appearance. As a control to each composition, granules were also produced in the same manner except that lactose was used instead of heavy magnesium carbonate and stored under the same conditions.

    ______________________________________                                                                    Changes in appear-                                                             ance after 1 week                                   Compound  Additive         at 50° C. and 75% RH                         ______________________________________                                         Compound (A)                                                                             Invention: Heavy magnesium                                                                      -                                                             carbonate                                                                      Control: Lactose ++                                                  Omeprazole                                                                               Invention: Heavy magnesium                                                                      -                                                             carbonate                                                                      Control: Lactose ++                                                  Timoprazole                                                                              Invention: Heavy magnesium                                                                      -                                                             carbonate                                                                      Control: Lactose                                                     Compound (C)                                                                             Invention: Heavy magnesium                                                                      -                                                             carbonate                                                                      Control: Lactose ++                                                  Compound (D)                                                                             Invention: Heavy magnesium                                                                      -                                                             carbonate                                                                      Control: Lactose ++                                                  ______________________________________                                          Notes:                                                                         -: No changes                                                                  ++: Severely                                                             

As is evident from the above results, the pharmaceutical compositions of the invention were all stable whether the active ingredient was the compound (A) omeprazole, timoprazole, the compound (C) or the compound (D).

EXPERIMENTAL EXAMPLE

Pharmaceutical compositions were produced in the same manner as in Examples 3 and 5 except that different basic inorganic Mg or Ca salts were used or that lactose was used as a control, and Example 6. After strage at 50° C. and 75% RH for 1 week or at 40° C. for 6 months, the compositions were observed for changes in appearance and for active ingredient constant (residual percentage).

                                      TABLE 2                                      __________________________________________________________________________                               50° C., 75%                                                                   40° C.                                  Additive             Initial                                                                             RH, 1 week                                                                           6 months                                       __________________________________________________________________________     Tablets made by the procedure of Example 3                                     Invention                                                                           Heavy magnesium                                                                          Appearance                                                                           White                                                                               No change                                                                            No change                                           carbonate Content                                                                              100% 98.0% 99.5%                                               Precipitated calcium                                                                     Appearance                                                                           White                                                                               No change                                                                            No change                                           carbonate Content                                                                              100% 97.4% 96.5%                                               Magnesium silicate                                                                       Appearance                                                                           White                                                                               No change                                                                            No change                                                     Content                                                                              100% 94.5% 95.0%                                          Control                                                                             No addition (lactose)                                                                    Appearance                                                                           Pale violet                                                                         Dark violet                                                                          Dark violet                                                   Content                                                                              100% 73.5% 82.1%                                          Granudles made by the procedure of Example 5                                   Invention                                                                           Heavy magnesium                                                                          Appearance                                                                           White                                                                               No change                                                                            No change                                           carbonate Content                                                                              100% 98.2% 99.1%                                               Precipitate calcium                                                                      Appearance                                                                           White                                                                               No change                                                                            No change                                           carbonate Content                                                                              100% 97.2% 98.6%                                               Magnesium oxide                                                                          Appearance                                                                           White                                                                               No change                                                                            No change                                                     Content                                                                              100% 99.1% 99.0%                                          Control                                                                             No addition (lactose)                                                                    Appearance                                                                           Pale violet                                                                         Dark violet                                                                          Dark violet                                                   Content                                                                              100% 84.2% 89.4%                                          Capsules of Example 7                                                          Invention                                                                           Heavy magnesium                                                                          Appearance                                                                           White                                                                               No change                                                                            No change                                           carbonate Content                                                                              100% 98.4% 99.1%                                          __________________________________________________________________________

The above results clearly indicate that the compositions of the invention show no changes in appearance at all and are stable in terms of the active ingredient content. 

We claim:
 1. A granule which comprises nonpareils coated with a mixture of a benzimidazole compound, a basic inorganic salt stabilizing agent and an additive.
 2. A granule of claim 1, wherein the basic inorganic salt stabilizing agent has a pH of not less than 7 when it is in the form of a 1% aqueous solution or suspension.
 3. A granule of claim 1, wherein the amount of the basic inorganic salt stabilizing agent relative to parts by weight of the benzimidazole compound is about 0.3 to 20 parts by weight.
 4. A granule of claim 1, wherein the basic inorganic salt stabilizing agent is a basic inorganic salt of magnesium.
 5. A granule of claim 1, wherein the basic inorganic salt stabilizing agent is a basic inorganic salt of calcium.
 6. A granule of claim 1, wherein the benzimidazole compound is a compound of the formula: ##STR8## wherein R¹ is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio or alkylsulfinyl;R² is hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl or alkylsulfonyl; R³ and R⁵ are the same or different and each is hydrogen, alkyl, alkoxy or alkoxyalkoxy; R⁴ is hydrogen, alkyl, alkoxy which may optionally be fluorinated, or alkoxyalkoxy; and m is an integer from 0 to
 4. 7. A granule of claim 1, wherein the benzimidazole compound is 2-[3-methyl-4-(2, 2,2-trifluoroethoxy-2-pyridyl)methylsulfinyl]benzimidazole. 